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A Depression Switch?

Deanna Cole-Benjamin never figured to be a test case for a radical new brain surgery for depression. Her youth contained no traumas; her adult life, as she describes it, was blessed. At 22 she joined Gary Benjamin, a career financial officer in the Canadian Army, in a marriage that brought her happiness and, in the 1990's, three children. They lived in a comfortable house in Kingston, a pleasant university town on Lake Ontario's north shore, and Deanna, a public-health nurse, loved her work. But in the last months of 2000, apropos of nothing -- no life changes, no losses -- she slid into a depression of extraordinary depth and duration.

"It began with a feeling of not really feeling as connected to things as usual," she told me one evening at the family's dining-room table. "Then it was like this wall fell around me. I felt sadder and sadder and then just numb."

Her doctor prescribed progressively stronger antidepressants, but they scarcely touched her. A couple of weeks before Christmas, she stopped going to work. The simplest acts -- deciding what to wear, making breakfast -- required immense will. Then one day, alone in the house after Gary had taken the kids to school and gone to work, she felt so desperate to escape her pain that she drove to her doctor's office and told him she didn't think she could go on anymore.

"He took one look," she told me later, "and said that he wanted me to stay right there in the office. Then he called Gary, and Gary came to the office, and he told us he wanted Gary to take me straight to the hospital."

They drove to the Providence Continuing Care Center's mental-health hospital, still known locally as the Kingston Psychiatric Hospital, or K.P.H., its name when it was built in the 1950's. "It's a dingy, archaic place," Deanna said, "typical of older mental hospitals." There, in the locked ward that also contained psychotic patients, she would spend the next 10 months straight and about 85 percent of the three years after that. Her depression would prove resistant to every class of antidepressant, numerous combinations of antidepressants and anti-anxiety drugs, intensive psychotherapy and about a hundred sessions of electroconvulsive therapy. Patients who have failed that many treatments usually don't emerge from their depressions.

Finally, in the spring of 2004, Deanna's psychiatrist at the hospital, Dr. Gebrehiwot Abraham, received a fax from a University of Toronto research team asking if he had an appropriate candidate for a clinical trial of a new, experimental surgery for treatment-resistant depression. The operation borrowed a procedure called deep brain stimulation, or D.B.S., which is used to treat Parkinson's. It involves planting electrodes in a region near the center of the brain called Area 25 and sending in a steady stream of low voltage from a pacemaker in the chest. One of the study's leaders, Dr. Helen Mayberg, a neurologist, had detected in depressed patients what she suspected was a crucial dysfunction in Area 25's activity. She hypothesized that the electrodes might modulate the area and ease the depression.

The procedure, Dr. Abraham told Deanna and Gary, had worked safely in thousands of Parkinson's patients. But it would carry some risk of neural complications (it was, after all, brain surgery), it would be uncomfortable and it might not work.

"We were in tears," said Deanna, who is now 41. "We felt we'd tried everything and nothing worked. But we talked about it and decided, 'Well, what have we got to lose?"'

What she hoped to lose, of course, was her depression. But depression, which 5 to 10 percent of Americans suffer in any given year and about 15 percent will suffer in their lifetimes, can be hard to lose. Drugs, as shown in a comprehensive study released last month by the National Institute of Mental Health, are effective in only half of patients with major depression. Psychotherapy does no better. For those people who are not helped by therapy or drugs, electroconvulsive therapy, or ECT, can bring relief. But few of those cures are complete. These therapies usually ease rather than cure depression while sometimes bringing side effects like insomnia or memory loss, and their potency often proves fleeting; as many as half to two-thirds of those successfully treated relapse within two years. Neither neuroscientists nor psychiatrists can say exactly what depression is. Neurologically and psychologically, what Hippocrates called the "black bile" and Susan Sontag "melancholy minus its charms" presents an almost impossibly complicated puzzle.

The expectations for the Toronto team's D.B.S. study were accordingly modest. When I later asked Mayberg's collaborator Dr. Andres Lozano, the neurosurgeon who performed the operations, what he had expected, he replied, "Nothing."

As it turned out, 8 of the 12 patients he operated on, including Deanna, felt their depressions lift while suffering minimal side effects -- an incredible rate of effectiveness in patients so immovably depressed. Nor did they just vaguely recover. Their scores on the Hamilton depression scale, a standard used to measure the severity of depression, fell from the soul-deadening high 20's to the single digits -- essentially normal. They've re-engaged their families, resumed jobs and friendships, started businesses, taken up hobbies old and new, replanted dying gardens. They've regained the resilience that distinguishes the healthy from the depressed.

These results brought a marvelous surprise to both the patients and the doctors involved -- and nervous anticipation about whether their luck will hold. Though a few of the patients are more than two years out from the surgery, none completely trust their cure. No one can tell them for sure that it will last, and they worry. The study doctors and the wider medical community, meanwhile, are guarded about whether D.B.S. will prove so effective in larger trials. "I can't emphasize enough that we need a large, randomized study to confirm this as a treatment," says Valerie Voon, a University of Toronto psychiatrist who was with the team for the first six patients and who is now a research fellow at the National Institutes of Health.

Those caveats notwithstanding, many scientists following the trial say they believe it will change how psychiatrists define and treat mood disorders. Mayberg, who speaks of a "paradigm shift," notes that she developed the trial to evaluate not a treatment but a hypothesis. In that sense the trial succeeded. Mayberg's focus on Area 25 tests the emerging "network" model of mood disorders, a new way of looking at psychiatric conditions that isn't restricted by the neurochemical model of mood that has dominated over the past quarter century or so. Rather, it incorporates neurochemistry into the concept of the brain as a circuit board or wiring diagram. The network model carries profound implications for research and, ultimately, treatment. The Prozac revolution showed everyone that tweaking neurochemistry can dampen and sometimes extinguish depression -- but only through a generalized approach, hitting the entire brain. ("Carpet-bombing," one neuroscientist calls it.) And the 50 percent success rate of antidepressant drugs suggests that they aren't hitting depression's central mechanism. The network approach, on the other hand, focuses on specific nodes, pathways and gateways that might be approached with various treatments -- electrical, surgical or pharmacological. This small trial appears to confirm this model so emphatically that it's already changing the neuropsychiatric view of the brain and the direction of research.

"People often ask me about the significance of small first studies like this," says Dr. Thomas Insel, who as director of the National Institute of Mental Health enjoys an unparalleled view of the discipline. "I usually tell them: 'Don't bother. We don't know enough.' But this is different. Here we know enough to say this is something significant. I really do believe this is the beginning of a new way of understanding depression."

When she started her research in the late 1980's, Helen Mayberg, too, looked at neurochemistry. "That's where biological psychiatry was then," she told me. "It was about the brain as a bowl of soup. You whip up a chemical, add it and stir. An alchemist point of view. But I soon realized I wanted to find out where things were changing."

Lively, smart and quick-witted, Mayberg talks of brain science with contagious excitement. She possesses just the kind of presence someone having a hole drilled in his head would welcome -- authoritative but warm. Mayberg originally considered becoming a psychiatrist, but she didn't like the discipline's resistance at the time (it was the 1970's) to neurological explanations of mood. So she became a behavioral neurologist, doing a residency at Columbia University and then moving to Johns Hopkins.

Setting aside the bowl-of-soup model did not mean deciding that neurochemicals weren't important. Rather it meant deciding that neurochemistry, and particularly the chemistry dictating how individual neurons communicate with one another, was probably driven by traffic between different brain areas, and that identifying the patterns in that traffic might yield new understanding. (Or, using another metaphor, if the brain is an orchestra, then the neurochemical approach focuses on how well individual players listen and respond to the players adjacent to them; the network approach, like a conductor, focuses on how the orchestra's sections -- strings, winds, brass, etc. -- coordinate and balance volume and tone. When both are working well, you've got music.)

Imaging tools for tracking these relationships, like PET scans and later functional magnetic resonance imagery, were just maturing as Mayberg pursued her work. Neuroscientists were soon using these tools to help identify networks involved in mental processes ranging from distinguishing facial expressions to experiencing alarm or pleasure. Each of these networks engages different brain areas in different combinations. The areas active in recognizing a fearful expression, for instance, won't match those for recalling old memories, though some areas might overlap. Defining the network involved in any given process requires figuring out not just which parts are involved but also which parts are most vital and how one affects another.

By the 1990's, Mayberg was trying to define the network that goes awry in depression. She and other researchers soon established that depression involved abnormal patterns of activity in a network that includes limbic areas (a cluster of evolutionarily older brain areas around the top of the brain stem), which control basic emotions and drives like fear, lust and hunger, and the newer cortex and subcortex responsible for thought, memory, motivation and reward.

Several researchers were working on this. But Mayberg, and, separately, Dr. Wayne Drevets, then at Washington University and now at the N.I.M.H., increasingly homed in on Area 25, which seemed crucial in both its behavior and its position in this network. They found that Area 25 was smaller in most depressed patients; that it lighted up in every form of depression and also in nondepressed people who intentionally pondered sad things; that it dimmed when depression was successfully treated; and that it was heavily wired to brain areas modulating fear, learning, memory, sleep, libido, motivation, reward and other functions that went fritzy in the depressed. It seemed to be a sort of junction box, in short, whose malfunction might be "necessary and sufficient," as Mayberg put it, to turn the world dim. Maybe it could provide a switch that would brighten the dark.

To work the switch, Mayberg needed a knife. In 1999 she moved from the University of Texas at San Antonio to the University of Toronto, where she met Lozano, who had become expert at using deep brain stimulation for treating Parkinson's, the neurological affliction that causes tremors and rigidity as well as cognitive and emotional declines. By the time he and Mayberg met, he'd slipped electrodes into the brains of almost 300 patients.

Depression is more elusive than Parkinson's. But approaching Area 25 with D.B.S. allowed the researchers to use a known tool. Neurosurgeons found as early as the 1950's that they could treat Parkinson's by destroying a small portion of the hyperactive globus pallidus, a brain area that is crucial to movement. The treatment illustrated one of the brain's many oddities: some areas can cause more trouble when they are excessively active than when they have no activity at all. In the early 1990's, surgeons increasingly began to use D.B.S. to quiet the globus pallidus by sending it steady, rapid pulses of low voltage. Patients' tremors would instantly ease or cease; their rigidity and uncontrollable body movements would fade over a week or two. Killing the current revived the symptoms. Surgeons have now implanted D.B.S. electrodes in some 30,000 Parkinson's patients worldwide. The procedure is not a cure-all. It helps some patients less than others, does little to alleviate Parkinson's cognitive and emotional decay and occasionally creates complications including infection, bleeding and memory loss. Its biggest problem may be its success. So many medical centers now do it that some do it badly or on poorly qualified patients. But done well, it usually works.

Mayberg knew all this from the literature and learned more in conversations with Lozano. She grew increasingly convinced that applying D.B.S. to Area 25 might control depression.

"So one day," she told me, "I went to Lozano and said: 'I want to turn off Area 25. Can we put a stimulator there and see if that does it?' And he goes, 'Why not?' "

Occasionally, Deanna felt good enough to go home. This feeling seldom lasted more than a few days. "You could tell she was getting bad again when she couldn't sleep," Gary said. "That was the red flag. She'd be around the house all night, watching TV, up worried, cleaning. Then she'd get worse each day. Her eyes got that sunken look. Those were the scariest times, when she was getting like that and I would drop the kids at school and go to work and know she was home alone."

During the bad periods, which was much of the time, Deanna thought about suicide almost constantly. Through the windows of the locked ward she could see Lake Ontario, cold and immense. While she was there, one patient managed to reach the lake, beyond the parking lot and a grove of trees, and drown himself. Deanna thought obsessively of doing the same.

"I imagined that all the time," she said. "That I would walk out there and walk into the lake and that would be it."

As the months and years passed and all treatments failed, it began to feel as if there were only one way out.

"It started to seem like, this is not going to stop," Gary said. "This is our life now. There were times I thought that it was going to end" -- he

looked across the table at Deanna -- "only when you committed suicide."

"The worst part for me," Deanna said, "was not being able to feel anything for my children. To hug them, to have them hug me, and feel nothing. That was devastating. An awful, awful place to be."

The D.B.S. operation involves an intrusion that is delicate but brutal. The patients are kept awake so they can describe any changes, and the only drug administered is a local anesthetic. The surgical team shaves much of the patient's head and attaches to the skull, with four screws drilled through skin into bone, the stereotactic frame that will hold the head steady against the operating table and serve as a navigational aid. Mounting the frame takes only about 10 minutes. But because it involves driving screws into the skull ("You can't truly feel it," as one patient said, "but you can hear it and see it and smell it"), and because it leaves you with a steel frame around the head, many patients find this the most distressing part of the whole business.

Gary found the frame more than he could take. He kissed his wife and went elsewhere, hoping she wouldn't be a vegetable when he next saw her. Then Deanna was rolled to an M.R.I. machine, where scans would be taken; the scans would help guide Lozano in placing the electrodes.

During the hour or so while the computer processed the scans, Deanna chatted with Mayberg. The day before, she told Mayberg, on video, that what she most wanted was to hold her children and feel it.

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When the scans were ready, she went to the operating room. She was placed on a table, which was tilted back like a La-Z-Boy. Lozano and his team bolted the stereotactic frame to the table, as it was described to me later. There was some scrubbing on her head, some chitchat among the surgical team, much fiddling with sterile drapes and instruments. Then Lozano fit a half-inch burred bit into a drill, turned it on and started drilling. He drilled right into the top of Deanna's skull, which brought a rattling sensation and a sound like that made by an air wrench removing the lugs off a car's wheel. Then he did it again.

Now Lozano threaded a guide tube -- "It's a straight shot," he said later, "really quite easy" -- down between crevices and seams to one side of Area 25, which is in two small lobes at the midline of the brain. He slid the first electrode and its lead down the tube, then repeated this for the other side. All this took nearly two hours. After he double-checked his locations, he wired the leads to a pacemaker and gave Mayberg a nod. They could turn it on anytime now.

Mayberg had squeezed into a spot at Deanna's side some time before. She had told Deanna that if anything felt different, she should say so. Mayberg wasn't going to tell her when the device was activated. "Don't try to decide what's important," Mayberg told her. "If your nose itches, I want to know." Now and then the two would chat. But so far Deanna hadn't said much.

"So we turn it on," Mayberg told me later, "and all of a sudden she says to me, 'It's very strange,' she says, 'I know you've been with me in the operating room this whole time. I know you care about me. But it's not that. I don't know what you just did. But I'm looking at you, and it's like I just feel suddenly more connected to you.' "

Mayberg, stunned, signaled with her hand to the others, out of Deanna's view, to turn the stimulator off.

"And they turn it off," Mayberg said, "and she goes: 'God, it's just so odd. You just went away again. I guess it wasn't really anything.'

"It was subtle like a brick," Mayberg told me. "There's no reason for her to say that. Zero. And all through those tapes I have of her, every time she's in the clinic beforehand, she always talks about this disconnect, this closeness and sense of affiliation she misses, that was so agonizingly painful for her to lose. And there it was. It was back in an instant."

Deanna later described it in similar terms. "It was literally like a switch being turned on that had been held down for years," she said. "All of a sudden they hit the spot, and I feel so calm and so peaceful. It was overwhelming to be able to process emotion on somebody's face. I'd been numb to that for so long."

It worked that way for other patients too. For those for whom it worked, the first surges of mood and sensation were peculiar to their natures. Patient 4, for instance, was fond of taking walks, and she had previously told Mayberg that she knew she was getting ill when whole landscapes turned dim, as if "half the pixels went dark." Her first comment when the stimulator went on was to ask what they'd done to the lights, for everything seemed much brighter. Patient 5, an elite bicycle racer before his depression, told me that a pulling that he had long felt in his legs and gut, "as if death were pulling me downward," had instantly ceased. Patient 1, who in predepression days was an avid gardener, amazed the operating room by announcing that she suddenly felt as if she were walking through a field of wildflowers. Two days after going home, she put a scarf over her shaved, stitched head, found her tools and went out to reclaim her long-neglected gardens.

Not all was light and flowers. On a purely biological level, the improvement made by D.B.S. sometimes amplified the side effects of the high doses of medication the patients had been taking. Doctors don't quite understand this phenomenon, but they see it happen in other instances too; it is as if the patient, deadened, is again made sensate. Deanna broke out in hives and felt nauseated; her hands shook. These symptoms eased when she (as several of the patients have done) reduced her meds -- slowly, so as not to introduce new variables. She now takes standard doses of Effexor, an antidepressant, and Seroquel, an anti-psychotic drug.

The cure also brought challenges at home. As with other disabilities, any partner turned caretaker gets used to calling the shots, and rearranging power, dependencies and expectations after a sudden recovery can prove hard. One patient, the cyclist, faced this challenge starkly, for he had started a relationship and married while he was depressed. "Frankly," he told me, "I'm not sure we've quite finished working this out." All the patients have benefited from coordinated assistance from psychiatrists, social workers and occupational therapists who try to smooth the transition.

"That help is crucial," says Mayberg, who is now a professor of psychiatry and neurology at Emory University in Atlanta. "We're just fixing the circuit. The patient's life still needs work. It's like fixing a knee. They need that high-quality physical and supportive therapy afterward if they're really going to move around again."

This transition is not back to a former self and family but to a new one. Gary Benjamin says he sees similar things in military families. "These soldiers get sent away for six months, they come back and all they want to do is return to their old home. But their old home isn't there, because everybody's changed. It takes some tough rearranging sometimes."

For a change so profound, these seem acceptable adjustments. And the treatment so far seems remarkably free of side effects. No one has suffered significant neural complications, probably because, unlike ECT, which sends 70 to 150 volts through the entire brain, these electrodes deliver only about 4 volts to an area about the size of a pea.

But what will happen when larger groups are treated? The team is continuing to operate on depressed patients, with a goal of 20. And would the successes stay high and the side effects low in a large, placebo-controlled trial? Neither Mayberg nor any of the other collaborators cares to guess. Other treatments have started this well and fizzled. For instance, vagus nerve stimulation, which sends a low current to the brain via a major nerve with connections to various brain areas, appeared to help about half of the patients in a small, initial, uncontrolled trial, but failed its only placebo-controlled trial. (In a controversial move, the Food and Drug Administration overruled its own reviewers and approved the device as a depression treatment anyway.)

"What if you do a hundred patients," I asked Mayberg one day, "and they do no better than placebo?"

"I suppose that's possible," she said. But she doesn't think that will be the case. The several authorities I talked to agree that the high success rate so far, along with the soundness of the theoretical base and D.B.S.'s track record with Parkinson's, suggests that this isn't just a lucky run.

"This just makes so much sense," says Dr. Antonio Damasio, director of the University of Southern California's Brain and Creativity Institute and a renowned neurologist, "and the weight of the results is so sizable. I would be surprised if they had no results with a larger body of patients."

On the other hand, even if it works, no one sees this becoming the new Prozac. The procedure costs too much (around $40,000) to use on anyone who hasn't tried everything else. The appropriate candidates for D.B.S. probably number in the thousands, not the millions. Perhaps the most sensible worry is that if the thing works, doctors might use it too freely, as they tend to do with successful new treatments; witness the problematic boom in D.B.S. for Parkinson's.

In the end, the procedure's greatest clinical value may lie in inspiring less intrusive ways of tweaking key nodes -- localized delivery of drug or gene therapies, or other means still to come. Such possibilities probably lie at least a decade away.

Regardless of how it pans out in the clinic, Mayberg and Lozano's D.B.S. study is already changing how neuroscientists and psychiatrists think about depression. One possibility, for instance, is that refining the networks that go awry in depression may reveal neurological subtypes of depression that can be diagnosed and treated differently. For example, Mayberg has already found that patients who respond well to Prozac usually show a change in their brain scans only a week after they start medication -- even though they don't feel a difference for 3 to 10 weeks (a long and sometimes dangerous wait). She's done preliminary work suggesting she might be able to identify such Prozac-friendly patients before they even start the drug. If she or others can replicate and elaborate on this diagnostic ability, doctors might be able to characterize a patient's depression and choose a best-odds therapy -- Prozac for one patient, talk therapy for a second, both for a third -- at the very beginning of treatment, savings weeks or months of trial and error.

The network model -- which some scientists also call a "systems" model -- also offers an organizing principle for research. Andreas Meyer-Lindenberg, a researcher with the N.I.M.H., points out that research on depression has so far followed clues left by drugs that were found to be effective only by chance. "We'd find a drug that helped depression, figure out how it works and make hypotheses from that about how the brain works," he says. The effectiveness of selective serotonin reuptake inhibitors (S.S.R.I.'s) like Prozac, for instance, inspired piles of research showing that mood regulation depends heavily on the availability of the neurotransmitter serotonin. (Neurotransmitters are chemicals that help carry messages across the spaces between neurons; S.S.R.I.'s treat depression by making more serotonin available in those spaces.)

This focus on neurotransmitters is the "bowl of soup" approach that Mayberg speaks of, and it has formed the bulk of depression research for more than two decades. Defining the networks the neurotransmitters move within, however -- and in particular identifying Area 25 as a key gateway within the depression network -- will let researchers bring their neurochemical knowledge to bear on specific targets.

"With this D.B.S. work," Meyer-Lindenberg says, "they have characterized in detail a system" -- or network -- "underlying a major disorder. It's not a simplistic thing where you're saying it's all about this one area and you inject a current and everything's fine. It's a very complicated system. But this D.B.S. work shows us that amid this complicated system there is a place of overlap, a common denominator" -- Area 25 -- "that's a very attractive treatment target." Here, Meyer-Lindenberg says, researchers can try to apply the knowledge they've gained about neurochemistry and genetics. The network theory presents a framework around which to apply these perspectives.

Meyer-Lindenberg's own work shows the power of this approach. Last June he published a study on the serotonin transporter gene, or sert gene, which helps determine serotonin availability. Other research had shown that people with the "short" version of the sert gene run more depression risk. Meyer-Lindenberg found a way to identify how various brain areas were affected by having that short version. Then he took 112 patients, half with the long version and half with the short, scanned their brains and asked the computer to find areas that scanned differently in the two groups. The area showing the most difference was Area 25.

Along with redirecting research, the quieting of Area 25 may also change our conception of depression from a condition in which something is lacking -- self-esteem, resilience, optimism, energy, serotonin, you name it -- to one in which an active agent makes a person sick.

"Most people think of depression as a deficit state," Mayberg says. "You're low, you're negative. But in fact, talk to a depressed person, and you have this bizarre combination of numbness and what William James called 'an active anguish.' 'A sort of psychical neuralgia,' he said, 'wholly unknown to healthy life.' You're numb but you hurt. You can't think, but you are in pain. Now, how does your psyche hurt? What a weird choice of words. But it's not an arbitrary choice. It's there. These people are feeling a particular, indescribable kind of pain."

This anguish, Mayberg suggests, is the manifestation of a neural circuit run amok. For doctors, establishing this should focus research and care. For those of us who've never known depression, recognizing it may help us see depression not as a dead absence but as a live affliction. We might even stop indulging the romantic notion of depression as intrinsic to one's identity. For this notion, too, was tested by Mayberg's experiment. When a steady, 4-volt thrum calmed these patients' anguish, they did not lose their identities. They regained them, feeling again the engagements with the world that most define them: flowers for the gardener, lightness for the cyclist and, for Deanna, a long-missed connection to others.

When Deanna, Gary and I finally finished talking, they insisted on driving me to my hotel. Halfway through town, Gary pulled off the main road, drove up a long, sinuous driveway and parked in a lot facing a dark, rambling building.

In the winter dark, the secure ward, off to the left, was easily discerned. It was a low wing, the only one with a few lights still on inside. Outside, bright flood lamps illuminated an exercise yard ringed by 20-foot-tall cyclone fencing topped with razor wire.

"And there's the lake," Gary said, motioning behind us. Through trees I could make out its blackness.